Co-signaling receptors regulate T-cell plasticity and immune tolerance

Shen, Haitao; Wu, Na; Nanayakkara, Gayani; Fu, Hangfei; Yang, Qian; Yang, William Y.; Li, Angus; Sun, Yu; Drummer, Charles; Johnson, Candice; Shao, Ying; Wang, Luqiao; Xu, Keman; Hu, Wenhui; Chan, Marion M.; Tam, Vincent C.; Choi, Eric T.; Wang, Hong; Yang, Xiaofeng

doi:10.2741/4710

Cited by 36 publications

(14 citation statements)

References 63 publications

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“…Since Mφs are prototypic professional antigen-presenting cells (APCs) that modulate CD4+ T cell activation by providing T cell activation signal #1 and co-stimulation/co-inhibition-based signal #2(50), we also examined the expression of 28 T cell co-stimulation and co-inhibition (immune checkpoint) receptors (23), including 14 co-stimulation receptors, 10 co-inhibition receptors, and 4 dual-functional (both co-stimulation and co-inhibition) receptors in tissue Mφ (Figure 3A), as we reported previously (49). As shown in Figure 3A, we found that: (i) the Mφ from LLSI express co-inhibition receptor CD274 (programmed death-ligand 1, PDL1) in much higher levels than ATMφ and (ii) the Mφ from peritoneum and ATMφ express lower levels of CD274 than BM Mφ.…”

Section: Resultsmentioning

confidence: 85%

Twenty Novel Disease Group-Specific and 12 New Shared Macrophage Pathways in Eight Groups of 34 Diseases Including 24 Inflammatory Organ Diseases and 10 Types of Tumors

et al. 2019

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The mechanisms underlying pathophysiological regulation of tissue macrophage (Mφ) subsets remain poorly understood. From the expression of 207 Mφ genes comprising 31 markers for 10 subsets, 45 transcription factors (TFs), 56 immunometabolism enzymes, 23 trained immunity (innate immune memory) enzymes, and 52 other genes in microarray data, we made the following findings. (1) When 34 inflammation diseases and tumor types were grouped into eight categories, there was differential expression of the 31 Mφ markers and 45 Mφ TFs, highlighted by 12 shared and 20 group-specific disease pathways. (2) Mφ in lung, liver, spleen, and intestine (LLSI-Mφ) express higher M1 Mφ markers than lean adipose tissue Mφ (ATMφ) physiologically. (3) Pro-adipogenic TFs C/EBPα and PPARγ and proinflammatory adipokine leptin upregulate the expression of M1 Mφ markers. (4) Among 10 immune checkpoint receptors (ICRs), LLSI-Mφ and bone marrow (BM) Mφ express higher levels of CD274 (PDL-1) than ATMφ, presumably to counteract the M1 dominant status via its reverse signaling behavior. (5) Among 24 intercellular communication exosome mediators, LLSI- and BM- Mφ prefer to use RAB27A and STX3 than RAB31 and YKT6, suggesting new inflammatory exosome mediators for propagating inflammation. (6) Mφ in peritoneal tissue and LLSI-Mφ upregulate higher levels of immunometabolism enzymes than does ATMφ. (7) Mφ from peritoneum and LLSI-Mφ upregulate more trained immunity enzyme genes than does ATMφ. Our results suggest that multiple new mechanisms including the cell surface, intracellular immunometabolism, trained immunity, and TFs may be responsible for disease group-specific and shared pathways. Our findings have provided novel insights on the pathophysiological regulation of tissue Mφ, the disease group-specific and shared pathways of Mφ, and novel therapeutic targets for cancers and inflammations.

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Section: Resultsmentioning

confidence: 85%

Twenty Novel Disease Group-Specific and 12 New Shared Macrophage Pathways in Eight Groups of 34 Diseases Including 24 Inflammatory Organ Diseases and 10 Types of Tumors

et al. 2019

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“…It has been reported that a Treg-specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) results in development of systemic lymphoproliferation, fatal autoimmune disease, hyperproduction of immunoglobulin E, and potent tumor immunity ( 130 ). Our previous report determined the expression of 28 co-signaling receptors in 32 human tissues in physiological/pathological conditions and found that the expression of inflammasome components are correlated with the expression of co-signaling receptors ( 19 ). We also reported that among 10 immune checkpoint receptors (ICRs), lung, liver, spleen and intestine macrophages (Mφ) and bone marrow (BM) Mφ express higher levels of CD274 (programmed cell death-1, PDL-1) than adipose tissue Mφ, presumably to counteract the M1 Mφ dominant status via its reverse signaling behavior ( 1 ), suggesting that tissue immune checkpoint receptor signaling may also modulate Tregs.…”

Section: Resultsmentioning

confidence: 99%

“…Immune responses including innate immune macrophages ( 1 ), antigen-specific responses ( 2 – 13 ), CD4 + Foxp3 + regulatory T cells (Treg) ( 14 – 18 ) and cosignaling- and immune checkpoint receptors ( 19 ) play significant roles in suppressing tumor growth and development. Although cancer immunotherapy is very promising ( 10 , 20 ), new anti-cancer drugs and vaccines fail to show promising benefits against cancer, which is at least partially due to the infiltration of Treg into the tumor region and suppression of anti-cancer activities of the drugs and vaccines ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, several important knowledge gaps remain: 1) are there differences in Treg transcriptomes between Tregs from normal lymphoid and non-lymphoid tissues, injured tissues, regenerative tissues, tissues from mouse carrying tumor, tumor tissues; 2) are secretomes generated in Tregs in various tissues and pathological conditions; and 3) how Treg transcription factor Foxp3, immune checkpoint receptors cytotoxic T lymphocyte associate protein-4 (CTLA-4, CD152) and programmed cell death-1 (PD-1, CD279) ( 19 ), immunometabolic pathways and innate immune memory (trained immunity) and ROS pathways regulate tissue Treg heterogeneity and Treg various secretomes. The major differences between our current study and previous reports on the roles of cytokines and chemokines in Treg are that secretome analyses provide a panoramic view on all the secreted genes in Treg, as opposed to focusing on only one or a few cytokines/chemokines ( 28 ).…”

Section: Introductionmentioning

confidence: 99%

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Canonical Secretomes, Innate Immune Caspase-1-, 4/11-Gasdermin D Non-Canonical Secretomes and Exosomes May Contribute to Maintain Treg-Ness for Treg Immunosuppression, Tissue Repair and Modulate Anti-Tumor Immunity via ROS Pathways

Tang

et al. 2021

Front. Immunol.

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We performed a transcriptomic analyses using the strategies we pioneered and made the following findings: 1) Normal lymphoid Tregs, diseased kidney Tregs, splenic Tregs from mice with injured muscle have 3, 17 and 3 specific (S-) pathways, respectively; 2) Tumor splenic Tregs share 12 pathways with tumor Tregs; tumor splenic Tregs and tumor Tregs have 11 and 8 S-pathways, respectively; 3) Normal and non-tumor disease Tregs upregulate some of novel 2641 canonical secretomic genes (SGs) with 24 pathways, and tumor Tregs upregulate canonical secretomes with 17 pathways; 4) Normal and non-tumor disease tissue Tregs upregulate some of novel 6560 exosome SGs with 56 exosome SG pathways (ESP), tumor Treg ESP are more focused than other Tregs; 5) Normal, non-tumor diseased Treg and tumor Tregs upregulate some of novel 961 innate immune caspase-1 SGs and 1223 innate immune caspase-4 SGs to fulfill their tissue/SG-specific and shared functions; 6) Most tissue Treg transcriptomes are controlled by Foxp3; and Tumor Tregs had increased Foxp3 non-collaboration genes with ROS and 17 other pathways; 7) Immune checkpoint receptor PD-1 does, but CTLA-4 does not, play significant roles in promoting Treg upregulated genes in normal and non-tumor disease tissue Tregs; and tumor splenic and tumor Tregs have certain CTLA-4-, and PD-1-, non-collaboration transcriptomic changes with innate immune dominant pathways; 8) Tumor Tregs downregulate more immunometabolic and innate immune memory (trained immunity) genes than Tregs from other groups; and 11) ROS significantly regulate Treg transcriptomes; and ROS-suppressed genes are downregulated more in tumor Tregs than Tregs from other groups. Our results have provided novel insights on the roles of Tregs in normal, injuries, regeneration, tumor conditions and some of canonical and innate immune non-canonical secretomes via ROS-regulatory mechanisms and new therapeutic targets for immunosuppression, tissue repair, cardiovascular diseases, chronic kidney disease, autoimmune diseases, transplantation, and cancers.

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“…Additionally, while miR155 -/mice exhibited fewer CD95 + CD86macrophages than WT mice (Supplementary Figure 4D), these mice had a higher percentage of CD95 + CD86macrophages at this extended time point compared with 12-week HFD. We recently reported that many of 28 T cell co-stimulatory receptors (CSRs), such as CD40, 4-1BBL, TL1A, CD30L, SLAM, CD48, SEMA4A, B7-1 (CD80), B7-2 (CD86), and CD155, are significantly upregulated in M1 macrophage polarization (47). This suggests a possibility that missing single CSR CD86, macrophages could still be polarized into pro-inflammatory macrophages such as CD95 + CD86macrophages as demonstrated here; and that although Fas/CD95 induces apoptosis, CD40 expressed in M1 macrophages may rescue pro-inflammatory macrophages from CD95-mediated apoptosis, as reported in B cells (48).…”

Section: High-fat Diet-fed Dko Mice (Metabolically Healthy Obesity Stmentioning

confidence: 99%

A Novel Subset of CD95+ Pro-Inflammatory Macrophages Overcome miR155 Deficiency and May Serve as a Switch From Metabolically Healthy Obesity to Metabolically Unhealthy Obesity

et al. 2021

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Metabolically healthy obesity (MHO) accounts for roughly 35% of all obese patients. There is no clear consensus that has been reached on whether MHO is a stable condition or merely a transitory period between metabolically healthy lean and metabolically unhealthy obesity (MUO). Additionally, the mechanisms underlying MHO and any transition to MUO are not clear. Macrophages are the most common immune cells in adipose tissues and have a significant presence in atherosclerosis. Fas (or CD95), which is highly expressed on macrophages, is classically recognized as a pro-apoptotic cell surface receptor. However, Fas also plays a significant role as a pro-inflammatory molecule. Previously, we established a mouse model (ApoE-/-/miR155-/-; DKO mouse) of MHO, based on the criteria of not having metabolic syndrome (MetS) and insulin resistance (IR). In our current study, we hypothesized that MHO is a transition phase toward MUO, and that inflammation driven by our newly classified CD95+CD86- macrophages is a novel mechanism for this transition. We found that, with extended (24 weeks) high-fat diet feeding (HFD), MHO mice became MUO, shown by increased atherosclerosis. Mechanistically, we found the following: 1) at the MHO stage, DKO mice exhibited increased pro-inflammatory markers in adipose tissue, including CD95, and serum; 2) total adipose tissue macrophages (ATMs) increased; 3) CD95+CD86- subset of ATMs also increased; and 4) human aortic endothelial cells (HAECs) were activated (as determined by upregulated ICAM1 expression) when incubated with conditioned media from CD95+-containing DKO ATMs and human peripheral blood mononuclear cells-derived macrophages in comparison to respective controls. These results suggest that extended HFD in MHO mice promotes vascular inflammation and atherosclerosis via increasing CD95+ pro-inflammatory ATMs. In conclusion, we have identified a novel molecular mechanism underlying MHO transition to MUO with HFD. We have also found a previously unappreciated role of CD95+ macrophages as a potentially novel subset that may be utilized to assess pro-inflammatory characteristics of macrophages, specifically in adipose tissue in the absence of pro-inflammatory miR-155. These findings have provided novel insights on MHO transition to MUO and new therapeutic targets for the future treatment of MUO, MetS, other obese diseases, and type II diabetes.

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Co-signaling receptors regulate T-cell plasticity and immune tolerance

Cited by 36 publications

References 63 publications

Twenty Novel Disease Group-Specific and 12 New Shared Macrophage Pathways in Eight Groups of 34 Diseases Including 24 Inflammatory Organ Diseases and 10 Types of Tumors

Twenty Novel Disease Group-Specific and 12 New Shared Macrophage Pathways in Eight Groups of 34 Diseases Including 24 Inflammatory Organ Diseases and 10 Types of Tumors

Canonical Secretomes, Innate Immune Caspase-1-, 4/11-Gasdermin D Non-Canonical Secretomes and Exosomes May Contribute to Maintain Treg-Ness for Treg Immunosuppression, Tissue Repair and Modulate Anti-Tumor Immunity via ROS Pathways

A Novel Subset of CD95+ Pro-Inflammatory Macrophages Overcome miR155 Deficiency and May Serve as a Switch From Metabolically Healthy Obesity to Metabolically Unhealthy Obesity

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